Effect of Signal Interference from Dosing Excipients on Pharmacokinetic Screening of Drug Candidates by Liquid Chromatography/Mass Spectrometry
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- 作者：Xinchun S. Tong ; Junying Wang ; Song Zheng ; James V. Pivnichny ; Patrick R. Griffin ; Xiaolan Shen ; Marcie Donnelly ; Ken Vakerich ; Chris Nunes ; and Judy Fenyk-Melody
- 刊名：Analytical Chemistry
- 出版年：2002
- 出版时间：December 15, 2002
- 年：2002
- 卷：74
- 期：24
- 页码：6305 - 6313
- 全文大小：186K
- 年卷期：v.74,no.24(December 15, 2002)
- ISSN：1520-6882
文摘
The effect of dosing vehicle excipients such as PEG400,propylene glycol, Tween 80, and hydroxypropyl-
-cyclodextrin on the accuracy of LC/MS measurements usedin pharmacokinetic studies is examined. Using PEG400as a probe compound, the concentration-time profile ofthe excipient in plasma from rats dosed both orally andintravenously is determined. These excipient plasmaconcentrations can result in a 2-5-fold increase incalculated plasma clearance values when the excipientinterferes with the quantitation of the dosed compound.This can result in false rejection of a compound in a drugdiscovery screen. Several plasma purification methodsand enhanced chromatographic selectivity are examinedas ways to minimize or avoid excipient effects, particularlyfor very polar compounds. The combination of efficientsample purification and selective chromatography provides an effective way to diminish the significant interference effects of PEG400 and Tween 80. When appropriate,using negative ion mode MS or changing a dosing vehicleexcipient, such as substituting propylene glycol forPEG400, provides an alternative approach for eliminatingsignal interference. The mechanism of excipient-relatedsignal interference is discussed in relation to both competition of gas-phase proton-transfer reactions and highviscosity of dosing excipients.
-cyclodextrin on the accuracy of LC/MS measurements usedin pharmacokinetic studies is examined. Using PEG400as a probe compound, the concentration-time profile ofthe excipient in plasma from rats dosed both orally andintravenously is determined. These excipient plasmaconcentrations can result in a 2-5-fold increase incalculated plasma clearance values when the excipientinterferes with the quantitation of the dosed compound.This can result in false rejection of a compound in a drugdiscovery screen. Several plasma purification methodsand enhanced chromatographic selectivity are examinedas ways to minimize or avoid excipient effects, particularlyfor very polar compounds. The combination of efficientsample purification and selective chromatography provides an effective way to diminish the significant interference effects of PEG400 and Tween 80. When appropriate,using negative ion mode MS or changing a dosing vehicleexcipient, such as substituting propylene glycol forPEG400, provides an alternative approach for eliminatingsignal interference. The mechanism of excipient-relatedsignal interference is discussed in relation to both competition of gas-phase proton-transfer reactions and highviscosity of dosing excipients.